Clinical samples from patients with acute or chronic non-A, B, C, D, E hepatitis in the United States are being studied for biological, serological or molecular evidence of transmissible agents. Patients with fulminant non-A, non-B hepatitis remain a diagnostic enigma and may be infected with one or more previously unrecognized viruses. We are attempting to discover the etiology of this disease. Evidence for the existence of an additional water-borne hepatitis virus has come from sero-epidemiologic studies in India and Saudi Arabia. We are attempting to transmit an agent from clinical specimens of such patients. Some years ago, a hepatitis virus was reported to be transmissible from a non-A, non-B hepatitis patient to marmoset (tamarin) monkeys. The agent, called the GB agent, could be serially transmitted in marmosets and was partially characterized. Recently the GB agent was cloned and sequenced and shown to be two separate viruses, each distantly related to hepatitis C virus as well as a previously unrecognized human virus. The GB agents and the newly discovered human virus are being studied in primates and in vitro. To date, the newly recognized human virus (HGV/GBV-C) has been transmitted to chimpanzees and the resulting infection characterized. In addition, several new viruses have been discovered in New World monkeys. These are being further characterized. Modern techniques of molecular biology have been used to discover new viruses in recent years. These are now being applied to prospectively collected sera from patients with transfusion-associated hepatitis in a search for new hepatitis viruses that may cause up to 15% of such hepatitis in the US.